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J. Biol. Chem., Vol. 280, Issue 13, 12593-12601, April 1, 2005

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Co-activation of ERK, NF-B, and GADD45 in Response to Ionizing Radiation^*

Tieli Wang, Yu-Chang Hu¶, Shaozhong Dong||, Ming Fan||, Daniel Tamae, Munetaka Ozeki, Qian Gao**, David Gius, and Jian Jian Li||

From the Division of Radiation Oncology, Beckman Research Institute and City of Hope National Medical Center, Duarte, California 91010, ^**Life Science Group, Bio-Rad Laboratories, Hercules, California 94583, Molecular Radiation Oncology, Radiation Oncology Sciences Program, Center for Cancer Research, NCI, National Institutes of Health, Bethesda, Maryland 20892, and the ^||Division of Molecular Radiobiology, Purdue University School of Health Sciences, West Lafayette, Indiana 47907

NF-B has been well documented to play a critical role in signaling cell stress reactions. The extracellular signal-regulated kinase (ERK) regulates cell proliferation and survival. GADD45 is a primary cell cycle element responsive to NF-B activation in anti-apoptotic responses. The present study provides evidence demonstrating that NK-B, ERK and GADD45 are co-activated by ionizing radiation (IR) in a pattern of mutually dependence to increase cell survival. Stress conditions generated in human breast cancer MCF-7 cells by the administration of a single exposure of 5 Gy IR resulted in the activation of ERK but not p38 or JNK, along with an enhancement of the NF-B transactivation and GADD45 expression. Overexpression of dominant negative Erk (DN-Erk) or pre-exposure to ERK inhibitor PD98059 inhibited NF-B. Transfection of dominant negative mutant IB that blocks NF-B nuclear translocation, inhibited ERK activity and GADD45 expression and increased cell radiosensitivity. Interaction of p65 and ERK was visualized in living MCF-7 cells by bimolecular fluorescence complementation analysis. Antisense inhibition of GADD45 strikingly blocked IR-induced NF-B and ERK but not p38 and JNK. Overall, these results demonstrate a possibility that NF-B, ERK, and GADD45 are able to coordinate in a loop-like signaling network to defend cells against the cytotoxicity induced by ionizing radiation.

Received for publication, September 24, 2004 , and in revised form, December 2, 2004.

^* This work was supported in part by National Institutes of Health RO1 Grant CA101990 and by the Office of Science, U. S. Department of Energy Grant DE-FG02-05ER63945 (to J. J. L.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by a Beckman Fellowship from the Beckman Foundation.

^¶ A visiting Radiation Oncologist from Veterans General Hospital-Causing, Taiwan.

To whom correspondence should be addressed: Division of Molecular Radiobiology, School of Health Sciences, Purdue University, Rm. 1279 Civil Engineering Bldg., 550 Stadium Mall Dr., West Lafayette, IN 47907. Tel.: 765-496-6792; Fax: 765-494-1377; E-mail: jjli{at}purdue.edu.

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